Process of producing



2,959,592 Patented Nov. 8, 1960 PnocEss or PRODUCING ,B-YOHIMBINEMaurice-Marie Janot, Robert Goutarel, and Alain Le Hir, Paris, France,assignors to Les Laboratoires Gobey, Paris, France, a corporation ofFrance No Drawing. Filed Feb. 19, 1959, Ser. No. 794,228 Claimspriority, application France Feb. 26, 1958 4 Claims. (Cl. 260-287) Thepresent invention relates to a process of preparing ,B-yohimbine fromyohimbinone.

In copending patent application Serial No. 794,226 filed February 19,1959 and entitled Yohimbinone and a Process of Making Same, there isdescribed a. simple process of preparing yohimbinone by oxidation ofyohimbine.

It is one object of the present invention to provide a simple andeffective process of converting said yohimbinone into B-yohimbine, acompound of valuable properties.

Other objects of the present invention and advantageous features thereofwill become apparent as the description proceeds.

The process according to the present invention has for its purpose andmakes possible the conversion of yohimbinone into B-yohimbine by aselective hydrogenation causing orientation of the C -hydroxyl group tothe fi-position, according to the following equation:

It is an advantage of the present invention that fi-yohimbine isproduced very easily with satisfactory yields.

In principle, the process according to the present invention consists inreducing yohimbinone by means of an alkali metal boronhydride or,respectively, by catalytic hydrogenation in the presence ofhydrogenation catalysts, such as, for instance, platinum oxide,palladium black, and the like. The less soluble fi-yohimbine is easilyisolated from the crude reduction product by fractional crystallizationat room temperature. The reaction is preferably carried out in awater-soluble solvent, such as methanol. The desired reduction productis obtained in substantially pure form by simple recrystallization.B-Yohimbine has interesting pharmacodynamic properties and is useful asintermediate in the preparation of valuable yohimbane derivatives.

The following examples serve to illustrate the present invention,without, however, limiting the same thereto. More particularly, theorder of introducing the reactants may be changed, the nature of thesolvents may be varied by using, for instance, tetrahydrofuran assolvent, other alkali metal boronhydrides may be employed than potassiumboronhydride, and other hydrogenation catalysts than those mentioned maybe used in accordance with the principles set forth herein and in theclaims annexed thereto. The melting points given in the examples areinstantaneous melting points determined on the Maquenne block.

Example 1 Reduction of yohimbinone to p-yohimbine by means of potassiumboronhydride.

5.00 g. of potassium boronhydride are added to 4 g. of yohimbinone in200 cc. of methanol. The reaction mixture is stirred for 4 hours at roomtemperature. After the addition of one 1. of water, the mixture isextracted with ether. The extracts are then dried over sodium sulfateand distilled to dryness. The residue is recrystallized from methanol.1.450 g. (36%) of fi-yohimbine of the melting point=235 C. (withdecomposition) and the optical rotation [a] =4S=i-2 (concentration: 1%in pyridine) are obtained. The compound is identical with the compounddescribed in the literature.

Working up of the mother liquors permits isolation of a supplementaryquantity of the desired compound.

Example 2 Catalytic hydrogenation of yohimbinone to B-yohimbine.

0.5 g. of platinum oxide, prepared according to Adams, are added to 1.5g. of yohimbinone in 500 cc. of alcohol at 96%. Hydrogenation takesplace with agitation at room temperature. The alcoholic solution is thenfiltered. B-Yohimbine is separated and purified as described above. 4-80mg. of c-yohimbine are obtained. The yield is 32% of the theoreticalyield.

In place of potassium boronhydride, used in Example 1, there may beemployed another alkali metal boronhydride, such as sodium boronhydrideor lithium boronhydride.

In place of methanol used as solvent in the reduction process by meansof an alkali metal boronhydride, there may be employed otherwater-soluble solvents, such as ethanol, dioxane, tetrahydrofuran, andothers.

We claim:

1. In a process of producing fi-yohimbine, the steps which comprisecatalytically hydrogenating yohimbinone in ethanol in the presence ofplatinum oxide and isolating fl-yohimbine from the hydrogenationproduct.

2. In a process of producing ,B-yohimbine, the steps which compriseadding an alkali metal boronhydride to yohimbinone in a solvent selectedfrom the group consisting of water-soluble lower alkanols, dioxane, andtetrahydrofuran, stirring the reaction mixture at room temperature untilreduction is completed, and isolating the resulting fi-yohimbine fromthe reduction mixture.

3. In a process of producing fi-yohimbine, the steps which compriseadding an alkali metal boronhydride to yohimbinone in methanol, stirringthe reaction mixture at room temperature until reduction is completed,and isolating the resulting fi-yohimbine from the reduction mixture.

4. In a process of producing pl-yohimbine, the steps which compriseadding potassium boronhydride to yohimbinone in methanol, stirring thereaction mixture at room temperature until reduction is completed, andisolating the resulting B-yohimbine from the reduction mixture.

References Cited in the file of this patent Bader: J. Am. Chem. Soc.,vol. 77, pp. 3547-3550 (1955).

1. IN A PROCESS OF PRODUCING B-YOHIMBINE, THE STEPS WHICH COMPRISECATALYTICALLY HYDROGENATING YOHIMBINONE IN ETHANOL IN THE PRESENCE OFPLATINUM OXIDE AND ISOLATING B-YOHIMBINE FORM THE HYDROGENATION PRODUCT.